Ovarian cancer is a deadly disease because most cases are diagnosed at advanced stages, when the cancer has already metastasized. Yet no effective diagnostic or screening tests are currently available for the early detection of ovarian cancer. The main reason for this failure is that little has been known about the early tumor process of this cancer. Though named ovarian cancer, the most deadly type, high-grade serous ovarian carcinoma (HGSC), appears to originate, not in the ovary, but instead in the fallopian tube. Beyond this emerging concept of tissue origin, yet most early tumor mechanisms still remain elusive, which poses a major roadblock to developing an effective diagnostic or screening test for early detection. Thus, the overall goal of this proposal is to improve our understanding on the molecular mechanisms of deadly ovarian cancer, especially the cell of origin, initiation, and progression of HGSC. Remarkably recapitulating deadly human high- grade serous ovarian cancer, the Dicer-Pten double-knockout (DKO) and p53-Dicer-Pten triple-mutant (TKO) mouse models will be instrumental in the proposed research. During the mentored K99 phase, the research will focus on employing and characterizing these DKO and TKO models. In particular, pre-clinical trials using DKO mice as well as cell-based assays using human ovarian cancer cell lines will be performed to evaluate the therapeutic potential of antiestrogen therapy in advanced ovarian cancer. Elucidating the cell of origin and early progression of HGSC will require cell-lineage tracing by mouse genetic fate-mapping analysis, which will begin in the K99 phase but be pursued extensively during the independent R00 phase. In addition, defining the role of p53 mutation in the initiation and early progression of HGSC will be investigated in detail by analyzing TKO mice and generating multiple p53 double-mutant mice during this independent phase. In pursuing these projects, Baylor College of Medicine, also part of the world-largest Texas Medical Center, offers extraordinary research and academic environments for my postdoctoral training and continuing development into an independent investigator. Coupled with my in-depth doctoral training in ovarian biology and also established collaborations with relevant experts, my extensive postdoctoral research experience in developing and analyzing mouse models of ovarian cancer will enable me to pursue and achieve the aims in the proposed research. This will undoubtedly lead to a successful career path as an independent investigator in cancer research with an emphasis on ovarian cancer. More important, the knowledge we will gain from these proposed studies will offer vital translational insights ? not only for the early detection and screening of ovarian cancer, but also for a new treatment for advanced ovarian cancer.